Genetic Variant CLNK:p.Val254Leu (chr4-10520803-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052964.4(CLNK):c.760G>T(p.Val254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V254M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CLNK
NM_052964.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.68

Publications

0 publications found

Variant links:

Genes affected

CLNK (HGNC:17438): (cytokine dependent hematopoietic cell linker) MIST is a member of the SLP76 family of adaptors (see LCP2, MIM 601603; BLNK, MIM 604515). MIST plays a role in the regulation of immunoreceptor signaling, including PLC-gamma (PLCG1; MIM 172420)-mediated B cell antigen receptor (BCR) signaling and FC-epsilon R1 (see FCER1A, MIM 147140)-mediated mast cell degranulation (Cao et al., 1999 [PubMed 10562326]; Goitsuka et al., 2000, 2001 [PubMed 10744659] [PubMed 11463797]).[supplied by OMIM, Mar 2008]

CLNK links:

ENSG00000287154 (HGNC:58732):

ENSG00000287154 links:

LOC105374482 (HGNC:):

LOC105374482 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.065384656).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052964.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLNK	NM_052964.4	MANE Select	c.760G>T	p.Val254Leu	missense	Exon 15 of 19	NP_443196.2	Q7Z7G1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLNK	ENST00000226951.11	TSL:1 MANE Select	c.760G>T	p.Val254Leu	missense	Exon 15 of 19	ENSP00000226951.6	Q7Z7G1-1
	ENSG00000287154	ENST00000663264.1		n.97-9331C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723230

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000300

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

85054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107304

Other (OTH)

AF:

0.00

AC:

AN:

60194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.024

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.049

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.56

M_CAP

Benign

0.0045

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

PhyloP100

-2.7

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.33

REVEL

Benign

0.016

Sift

Uncertain

0.027

Sift4G

Benign

0.25

Polyphen

0.52

Vest4

0.075

MutPred

0.16

Gain of catalytic residue at V254 (P = 0.045)

MVP

0.040

MPC

0.0066

ClinPred

0.12

GERP RS

-1.5

Varity_R

0.051

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over